It has been recognized, since the beginning of the AIDS epidemic, that HIV infection frequently affects the brain leading to dementing illness. Although it is clear that neurons that degenerate are not infected with the virus but rather are susceptible to viral proteins and cellular products released y infected cells, it remains unclear what host factors may regulate this neuronal susceptibility. Similar to other neurodegenerative diseases, HIV dementia occurs at greater frequency in post menopausal women. Since estrogens have been shown to be neuroprotective in several neurodegenerative diseases, and women with HIV infection may develop gonadal failure, it is important to determine if estrogens may similarly protect against the neurotoxic effects of HIV proteins and what the underlying mechanisms for such effects may be. Indeed preliminary data from our laboratory supports a neuroprotective role for estrogen against HIV protein-induced neurotoxicity. Through a highly interactive project we will determine if HIV proteins can modulate the expression of estrogen receptors in brain cells and if the neuroprotective effects of estrogens are mediated via estrogen receptors or via non-receptor mediated mechanisms. We will drawn upon the strengths of several well established investigators in complementary areas of expertise namely, HIV protein neurotoxicity, gonadal hormone effects on brain and in vivo model systems of neurotoxicity to enhance the careers of junior investigators. This proposal will use novel techniques such as human and murine models, estrogen receptor knock out animals and novel molecular techniques to address these questions. Novel experimental models will also be generated through interactions with other projects. Results derived from this project will have wide implications for the prevention/treatment of HIV dementia in women.